Method of evaluating pharmaceutical preparation containing luliconazole and index substance

ABSTRACT

Disclosed is a method of evaluating stability of a pharmaceutical preparation containing luliconazole. The method includes measuring an amount of production of an SE form of luliconazole represented by following formula (2), an amount of production of a Z form of luliconazole represented by following formula (3) and an amount of production of an amide form of luliconazole represented by following formula (1) after storage under a severe condition or an accelerated condition, and judging that the stability of the pharmaceutical preparation is high if each of the amount of production of the SE form, the amount of production of the Z form and the amount of production of the amide form is not more than 5% by weight with respect to a compounded amount of luliconazole.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of Japan application serialno. 2013-256584, filed on Dec. 12, 2013. The entirety of theabove-mentioned patent application is hereby incorporated by referenceherein and made a part of this specification.

TECHNICAL FIELD

The present invention relates to a method of evaluating stability of apharmaceutical preparation containing luliconazole and to an indicator(index substance) which is useful for the method, and the indexsubstance includes an amide form.

BACKGROUND ART

Luliconazole is an antifungal agent which is excellent in the action onfungi. At present, luliconazole is widely used as a pharmaceutical ormedicine for tinea pedis and tinea corporis, and it is going to beapplied also for the action on tinea unguium as well. Known problemswhich should be solved in relation to the pharmaceutical preparation ofluliconazole include that luliconazole is converted to the stereoisomerssuch as the SE form or the Z form, and that the crystallization ofluliconazole is caused immediately after the application (see, forexample, Patent Documents 1 to 6).

PRECEDING TECHNICAL DOCUMENTS Patent Documents

-   Patent Document 1: WO2007/102241;-   Patent Document 2: WO2007/102242;-   Patent Document 3: WO2007/102243;-   Patent Document 4: WO2009/31642;-   Patent Document 5: WO2009/31643;-   Patent Document 6: WO2009/31644.

SUMMARY OF THE INVENTION Technical Problem

However, nothing is known about the presence of an amide form of theluliconazole represented below. Further, nothing is known at all as wellabout the fact that the presence or absence of the production of thissubstance becomes an important problem to select a solvent in thepharmaceutical preparation.

Further, it is considered that this amide form is produced by theaddition of water with respect to a cyano group of the luliconazole.However, contrary to the speculation of the presence of the amide form,the amide form is hardly produced even if a luliconazole as an activeingredient undergoes an accelerated test and/or a severe test. Namely,the presence of the amide form is speculated; however, the substancethereof has not been understood. Accordingly, it is difficult tospeculate in the stage of manufacturing the pharmaceutical preparationthat such a compound may be produced under a storage condition dependingon the type of the solvent. Further, as the SE form and the Z form arerelatively readily produced by the accelerated test and/or the severetest, the production mechanism of the amide form is considered differentfrom those of the SE form and the Z form.

On the other hand, when a pharmaceutical preparation of luliconazole ismanufactured, the present inventors have experienced that a relatedsubstance, which is different from the SE form and the Z form, appearsdepending on the type of the selected solvent. Such recognition has beenobtained that the key of the manufacturing of a pharmaceuticalpreparation of luliconazole is to specify the related substance andclarify the relationship with respect to the pharmaceutical preparationcomponents.

The present invention has been made in the circumstances as describedabove, an object of which is to provide a technique to improve thestability of a pharmaceutical preparation containing luliconazole.

Solution to Problem

Taking the foregoing circumstances into consideration, the presentinventors have repeatedly performed diligent researches and efforts inorder to seek a technique to improve the stability of a pharmaceuticalpreparation containing luliconazole. As a result, it has been found outthat the time-dependent production of an amide form is present as afactor of inhibiting the stability of a pharmaceutical preparationcontaining luliconazole. That is, in a luliconazole pharmaceuticalpreparation, it is possible that an amide form may be produced dependingon the types of constituent components of the preparation, independentlyfrom the production of the SE form and the Z form. It has been found outthat more stable pharmaceutical preparation containing luliconazole maybe obtained by adding an amount of production of such an amide form asan stability index together with an amount of production of the SE formand the Z form of luliconazole to evaluate the stability.

That is, the present invention is as follows.

<1> A method of evaluating stability of a pharmaceutical preparationcontaining luliconazole, comprising:

-   -   measuring an amount of production of an SE form of luliconazole        represented by following formula (2), an amount of production of        a Z form of luliconazole represented by following formula (3)        and an amount of production of an amide form of luliconazole        represented by following formula (1) after storage under a        severe condition or an accelerated condition, and judging that        the stability of the pharmaceutical preparation is high if each        of the amount of production of the SE form, the amount of        production of the Z form and the amount of production of the        amide form is not more than 5% by weight with respect to a        compounded amount of luliconazole.

<2> The evaluation method according to <1>, wherein each of the amountof production of the SE form, the amount of production of the Z form andthe amount of production of the amide form is not more than 0.2% byweight with respect to the compounded amount of luliconazole.

<3> The evaluation method according to <1> or <2>, wherein the severecondition and the accelerated condition are 60° C. for 3 weeks and 40°C. for 6 months, respectively.

<4> The evaluation method according to any of <1> to <3>, wherein thepharmaceutical preparation containing luliconazole comprises one or moreof a component selected from polyhydric alcohol or ether thereof,dibasic acid ester, aromatic alcohol, ketone, triglyceride andheterocyclic solvent.

<5> The evaluation method according to <4>, wherein

-   -   the polyhydric alcohol or the ether thereof is selected from        propylene glycol, polyethylene glycol, 1,3-butanediol,        diethylene glycol monoethyl ether, diethylene glycol diethyl        ether and polypropylene glycol;    -   the dibasic acid ester is selected from diethyl adipate,        diisopropyl adipate and propylene carbonate;    -   the aromatic alcohol is benzyl alcohol;    -   the ketone is acetone or methyl ethyl ketone;    -   the triglyceride is medium chain fatty acid triglyceride or        olive oil; and    -   the heterocyclic solvent is N-methyl-2-pyrrolidone or        N-ethyl-2-pyrrolidone.    -   <6> A pharmaceutical medicament preparation, comprising:    -   1) luliconazole; and    -   2) one or more components selected from polyhydric alcohol or        ether thereof, dibasic acid ester, aromatic alcohol, ketone,        triglyceride and heterocyclic solvent, wherein    -   upon measurement of an amount of production of an SE form of        luliconazole represented by following formula (2), an amount of        production of a Z form of luliconazole represented by following        formula (3) an amount of production of an amide form of        luliconazole represented by following formula (1) by storage        under a severe condition and an accelerated condition, each of        the amount of production of the SE form, the amount of        production of the Z form and the amount of production of the        amide form is not more than 5% by mass with respect to a        compounded amount of luliconazole.

<7> The pharmaceutical medicament preparation according to <6>, whereineach of the amount of production of the SE form, the amount ofproduction of the Z form and the amount of production of the amide formafter storage under the severe condition and the accelerated conditionis not more than 0.2% by mass with respect to the compounded amount ofluliconazole.

<8> An index substance of the stability of a pharmaceutical preparationcontaining luliconazole, the index substance including an amide form ofthe luliconazole indicated in following formula (1), wherein the indexsubstance of the stability complements the evaluation of the stabilitythat uses an SE form of luliconazole represented by following formula(2) and a Z form of luliconazole represented by following formula (3) asindex substances.

<9> An amide form of luliconazole represented by following chemicalformula (1).

Advantageous Effects of Invention

The present invention can provide a technique to improve the stabilityof a pharmaceutical preparation containing luliconazole.

DESCRIPTION OF EMBODIMENTS

<1> Evaluation Method of the Present Invention

The present invention relates to the method of evaluating the stabilityof a pharmaceutical preparation containing luliconazole. The methodincludes measuring an amount of production of the SE form ofluliconazole of the above-indicated structure, an amount of productionof the Z form of luliconazole of the above-indicated structure and anamount of production of the amide form of luliconazole of theabove-indicated structure after storage under a severe condition or anaccelerated condition, and judging that the stability of thepharmaceutical preparation is high if each of the amount of productionof the SE form, the amount of production of the Z form and the amount ofproduction of the amide form is small.

The severe condition herein refers to a storage condition at 60° C. for3 weeks, and the accelerated condition herein refers to a storagecondition at 40° C. for 6 months. The stability of a pharmaceuticalpreparation containing luliconazole has shown very good consistencybetween the severe condition and the accelerated condition. Accordingly,either of the conditions can be used. Further, the storage at 40° C. for6 months is known as a condition substitutable for the condition at aroom temperature for 3 years in an application for manufacturingapproval of a pharmaceutical.

The amide form([R-(E)]-α-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1H-imidazole-1-acetamide)of luliconazole is very hardly produced by decomposition and the like ofa luliconazole active ingredient, and is hardly produced by the severetest or the accelerated test of the luliconazole as the activeingredient. It is known that water is usually readily added to a cyanogroup by an acid or a base and the amide form is thereby produced.However, this generality is not applicable in the case of luliconazole,for the following reason. It is considered that a cyano group is stablebecause of a conjugated structure thereof continuing from a dithiolanering to a side chain double bond, an imidazolyl group attached to theside chain double bond and a substituted phenyl group attached to thedithiolane ring. Therefore, whether each of an amount of production ofthe SE form and an amount of production of the Z form under theaccelerated condition or the severe condition is large or small has beenused as an index of the stability of luliconazole.

However, in the process of researching the manufacturing of thepharmaceutical preparation, the present inventors have recognized thatthe amide form is produced after the storage of the pharmaceutical underthe accelerated condition or the severe condition by being affected bycomponents blended therein, independently from the amount of productionof the SE form and the amount of production of the Z form under theaccelerated condition or the severe condition, and have found out that,in a case where the component to be blended is changed, an amount ofproduction of the amide form should be used as an index of the stabilityin addition to an amount of production of the SE form and an amount ofproduction of the Z form.

The amide form of luliconazole is produced by treating luliconazoletogether with water in the presence of a metal catalyst such as copper,iridium, alumina and hydroxyapatite. Alternatively, the amide form isalso obtained by making an acid or an alkali to act on luliconazole inwater-containing ethanol. However, it is preferred that a catalyst asmentioned above is present. The amide form thus obtained is purified bymeans of, for example, the chromatography such as silica gel columnchromatography, octadecyl modified silica gel column chromatography orthe like and/or the recrystallization from a mixture solution of ethylacetate and normal hexane, ethanol, isopropanol or the like, and theamide form is provided as the index substance. Since the amide form ofluliconazole is, as mentioned above, a substance which is difficult toproduce under normal conditions, it is preferable to undergo a reactionunder the presence of a catalyst as mentioned above. Even if thereaction is under the presence of such a catalyst, a purificationprocess by means of column chromatography and the like is required asthe ratio of conversion to the amide form is low. As for the indexsubstance, it is preferable that the purity is not less than 90%.

Such a component can be confirmed by means of HPLC. When the relatedsubstance of luliconazole is confirmed, a chiral normal phase column isused in many cases in order to distinguish luliconazole and the isomersuch as the SE form or the Z form. However, the amide form representedby the chemical formula (1) is hardly detected under the elutioncondition for the chiral normal phase column. Therefore, it ispreferable to perform the investigation under such a condition that areverse phase column, which is based on the use of cation-capturingcounterion such as alkylsulfonate or the like, is used. Such an analysiscondition is preferably exemplified by the following. Under such acondition, it is also possible to detect main related substances such asthe SE form, the Z form or the like together with luliconazole. Byadopting such a method, it is possible to simultaneously measure thethree index substances of the evaluation method of the presentinvention. Such three index substance, namely the SE form, the Z formand the amide form, can be measured by means of HPLC with a followingcondition.

Column: Inertsil ODS-2 4.6×150 mm, column temperature: 40° C., mobilephase: solution of 0.13% sodium undecan-1-sulfonate mixture(water/acetonitrile/acetic acid (100) (54:45:1, v/v/v)), flow rate: 1.0mL/min., detection: 295 nm.

The subject of the evaluation method of the present invention is apharmaceutical preparation containing luliconazole. When apharmaceutical preparation of luliconazole is prepared, the amide formrepresented by the chemical formula (1) is produced during the storageat a high temperature of 40 to 60° C. depending on the type of theselected solvent. The antifungal activity of the amide form itself islow. Therefore, the production of the amide form results in the decreasein the activity of the pharmaceutical preparation.

It has been grasped that the addition of polyhydric alcohol such as1,3-butanediol is the factor of the production of such an amide form.Other than polyhydric alcohol, it is possible to exemplify, for example,dibasic acid ester such as diethyl adipate, aromatic alcohol such asbenzyl alcohol, ketone such as acetone and methyl ethyl ketone,triglyceride such as medium chain fatty acid triglyceride, andheterocyclic solvent such as N-methyl-2-pyrrolidone as the solvent withwhich the amide form may be produced.

If such an index substance is increased in the prepared pharmaceuticalpreparation, an amount of production of the amide form as describedabove can be changed by separating the solvent and substituting thesolvent which may cause production of an amide form such as polyhydricalcohol with another solvent. Thus, it is possible to secure thestability of the pharmaceutical preparation.

The following guideline on the stability of this pharmaceuticalpreparation can be exemplified. That is, an amount of production of theamide form is preferably not more than 10% by mass, more preferably notmore than 5% by mass, much more preferably not more than 1% by mass, andstill much more preferably not more than 0.5% by mass with respect to acompounded amount of luliconazole after the storage at 40° C. for 6months (accelerated condition) or the storage at 60° C. for 3 weeks(severe condition), for the following reason. That is, within thisrange, substantially no influence is exerted on the activity of thepharmaceutical preparation. Furthermore, if an amount of production isnot more than 0.2% by mass, the degree of contribution as a relatedsubstance is small. Any active pharmaceutical ingredient-relatedsubstance within such an amount range is not classified into the relatedsubstance according to the Pharmaceutical Affairs Law in Japan.

Further, the content of the amide form represented by the chemicalformula (1) as described above can be measured to evaluate a product,and thus, the evaluation can guarantee the quality of the product. Insuch a case, it is preferable that the operation for measuring thecontent of the amide form represented by the chemical formula (1) isincorporated into the production step concerning the quality of theproduct. The production step concerning the quality of the product ispreferably exemplified, for example, by the step of dissolvingluliconazole in the solvent or the like. It is also preferable that theoperation for measuring the content of the amide form is incorporatedinto the storage step for the produced product.

It is also preferable that an amount of production of the SE form and/oran amount of production of the Z form are/is also measured together withthe above measuring step by means of a chiral column to control theproduction thereof in order to improve the quality of the product, forthe following reason. That is, in particular, since the productionmechanism of the SE form and the production mechanism of the Z form aredifferent from each other and also different from the productionmechanism of the amide form, only suppressing the production of any oneof the SE form, Z form and amide form could lead to an increase in theother related substances.

The SE form or the Z form can be measured by means of HPLC under afollowing HPLC condition. In a final product, each of the amide formrepresented by the chemical formula (1), the SE form represented by thechemical formula (2) and the Z form represented by the chemical formula(3) is preferably not more than 5% by mass, more preferably 1% by mass,much more preferably not more than 0.5% by mass, and still much morepreferably not more than 0.2% by mass with respect to a compoundedamount of luliconazole. Such a pharmaceutical medicament preparation isa preferable mode of the pharmaceutical medicament preparation of thepresent invention. In such a mode, long-term stability can be secured.

<Measurement Condition of SE Form and Z Form>

HPLC condition: Column: CHIRALCEL OD-RH 4.6×150 mm, column temperature:35° C., mobile phase: mixture of methanol/1.8% potassiumhexafluorophosphate solution (83:17, v/v)), flow rate: 0.56 mL/min.,detection: 295 nm.

Polyhydric alcohol is exemplified as a solvent that is used for apharmaceutical preparation containing luliconazole. In general,1,3-butanediol, propylene glycol, polyethylene glycol, polypropyleneglycol, polyoxyethylene-polyoxypropylene glycol and glycerin can beexemplified as the polyhydric alcohol. Alkyl ethers having 1 to 4 carbonatoms can be preferably exemplified as an ether form thereof.Specifically, diethylene glycol monoethyl ether, diethylene glycoldiethyl ether and the like can be exemplified.

The degree of polymerization of the polymer is usually about 2 to 50,and preferably 3 to 30.

Among the above, 1,3-butanediol usually has an intense tendency tofacilitate the production of an amide form. Even in the case ofpolyhydric alcohol, for example, polyethylene glycol and polypropyleneglycol have a weak tendency thereof, and rather have a tendency ofsuppressing the production of an amide form compared with the1,3-butanediol. Therefore, when the amide form is considerably producedin a pharmaceutical preparation containing 1,3-butanediol, theproduction of the amide form can be suppressed by substituting1,3-butanediol with polyethylene glycol and/or polypropylene glycol.

In order to achieve the suppression as described above, in the case ofpolyethylene glycol, it is possible to exemplify that polyethyleneglycol is contained preferably by 20 to 50% by mass, and more preferablyby 28 to 35% by mass with respect to the total amount of thepharmaceutical preparation. On the other hand, polypropylene glycol iscontained preferably by 15 to 40% by mass and more preferably by 17 to25% by mass with respect to the total amount of the pharmaceuticalpreparation, for the following reason. That is, if the content isexcessively large, the compatibility with respect to luliconazole isdeteriorated in some cases. If the content is excessively small, theeffect to suppress the amide form is not recognized. When theconstruction as described above is used, then it is possible to suppressthe production of the amide form, and an amount of production of theamide form can be suppressed to be not more than 10% by mass, morepreferably not more than 5% by mass, much more preferably not more than1% by mass, still much more preferably not more than 0.5% by mass andyet more preferably not more than 0.2% even under the acceleratedcondition at 40° C. for 6 months or under the severe condition at 60° C.for 3 weeks. As such, polyhydric alcohol or ether thereof comprises acomponent that facilitates the production of an amide form and acomponent that suppresses the production of an amide form; therefore, itis necessary to confirm the stability by means of the evaluation methodof the present invention.

The polyhydric alcohol that is used for a pharmaceutical preparationcontaining luliconazole to which the evaluation method of the presentinvention is applied, can be preferably exemplified by a polyhydricalcohol selected from propylene glycol, polyethylene glycol,1,3-butanediol, diethylene glycol monoethyl ether, diethylene glycoldiethyl ether and polypropylene glycol. Polyhydric alcohol is containedpreferably by 5 to 70% by mass with respect to the total amount of thepharmaceutical preparation.

A single general concept including a component facilitating theproduction of an amide form and a component suppressing the productionthereof can be exemplified by a solvent.

A solvent that can be used for a pharmaceutical preparation containingluliconazole can be preferably exemplified, other than polyhydricalcohol, for example, dibasic acid ester such as propylene carbonate,diethyl adipate, diisopropyl adipate and diethyl sebacate; aromaticalcohol such as benzyl alcohol and phenethyl alcohol; ketone such asacetone and methyl ethyl ketone; triglyceride such as medium chain fattytriglyceride and olive oil; or heterocyclic solvent such asN-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone,N-butyl-2-pyrrolidone and pyrrolidone carboxylate.

In particular, dibasic acid ester is preferably selected from diethyladipate, diisopropyl adipate and propylene carbonate; benzyl alcohol ispreferable as aromatic alcohol; N-methyl-2-pyrrolidone orN-ethyl-2-pyrrolidone is particularly preferable as the heterocyclicsolvent; acetone or methyl ethyl ketone is preferable as ketone; andmedium chain fatty acid triglyceride or olive oil is preferable astriglyceride. A Solvent such as dibasic acid ester, aromatic alcohol,ketone, triglyceride and heterocyclic solvent is contained preferably by1 to 30% by mass with respect to the total amount of the pharmaceuticalpreparation.

<2> Pharmaceutical Preparation of the Present Invention

The pharmaceutical medicament preparation of the present invention is apharmaceutical medicament preparation containing: 1) luliconazole; and2) one or more components selected from polyhydric alcohol or etherthereof, dibasic acid ester, aromatic alcohol, ketone, triglyceride andheterocyclic solvent. The pharmaceutical medicament preparation ischaracterized by that an amount of production of the SE form indicatedabove, an amount of production of the Z form of luliconazole indicatedabove and an amount of production of the amide form of luliconazoleindicated above after storage under the severe condition or theaccelerated condition are measured, and each of the amount of productionof the SE form, the amount of production of the Z form and the amount ofproduction of the amide form is not more than 5% by mass with respect tothe compounded amount of luliconazole.

Luliconazole can be synthesized according to, for example, a methoddescribed in Japanese Patent Application Laid-Open Publication No. 60(1985)-218387. That is, 1-cyano-methyl imidazole and carbon disulfideare reacted to obtain a compound (III) which is subsequently reactedwith a compound of a general formula (II) having a leaving group tothereby obtain a compound represented by a general formula (1) asfollows. As the leaving group, for example, a methanesulfonyloxy group,a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a halogen atomand the like can be preferably exemplified.

In the formula, Y and Y′ represent the leaving group such as amethanesulfonyloxy group, a benzenesulfonyloxy group, ap-toluenesulfonyloxy group or a halogen atom, and M represents alkalimetal. R and X represent Cl.

The content of luliconazole in the pharmaceutical medicament preparationof the present invention is preferably 0.1 to 20% by mass, morepreferably 0.5 to 15% by mass, and much more preferably 1 to 10% bymass.

Such a pharmaceutical preparation preferably contains: polyhydricalcohol or the ether thereof selected from propylene glycol,polyethylene glycol, 1,3-butanediol, diethylene glycol monoethyl ether,diethylene glycol diethyl ether and polypropylene glycol; dibasic acidester selected form diethyl adipate, diisopropyl adipate and propylenecarbonate; benzyl alcohol as aromatic alcohol; N-methyl-2-pyrrolidone orN-ethyl-2-pyrrolidone as a heterocyclic solvent; acetone or methyl ethylketone as ketone; and medium chain fatty acid triglyceride or olive oilas triglyceride. The pharmaceutical preparation containing such acomposition is characterized by that the amide form is controlledpreferably by not more than 5% by mass, more preferably by not more than1% by mass, much more preferably by not more than 0.5%, and still muchmore preferably by not more than 0.2% by mass after storage under theaccelerated condition or the severe condition with respect to acompounded amount of luliconazole. The pharmaceutical medicamentpreparation of the present invention is characterized by that, inaddition to the amide form, each of the SE form and the Z form iscontrolled preferably by not more than 5% by mass, more preferably bynot more than 1% by mass, much more preferably by not more than 0.5%,and still much more preferably by not more than 0.2% by mass afterstorage under the accelerated condition or the severe condition. Such apharmaceutical medicament preparation is obtained as a product of theevaluation method of the pharmaceutical medicament preparation of thepresent invention.

The pharmaceutical preparation of the present invention can bemanufactured by appropriately adding, in addition to luliconazole andthe solvents described above, other solvents, colorants, antioxidants,chelating agents, emulsifying and dispersing agents, solubilizing agentssuch as polyvinyl pyrrolidone, disintegrating agents, excipients,binding agents, coating agents, flavoring agents, and stabilizers suchas lactic acid, and by treating the foregoing components in accordancewith an ordinary method.

The pharmaceutical medicament preparation of the present invention ispreferably used to treat or cure the disease caused by any fungus orprevent the deterioration of the disease by utilizing the characteristicof luliconazole. The disease caused by any fungus can be exemplified bytinea pedis such as athlete's foot, tinea corporis such as candidiasisand tinea versicolor, and trichophytosis of hard keratin portion such astinea unguium. It is especially preferable to use the pharmaceuticalmedicament preparation of the present invention for treating the diseaseof the hard keratin portion such as tinea unguium, because the effectthereof is remarkable. The effect of the pharmaceutical medicamentpreparation of the present invention is expressed on the nail especiallypreferably. However, the effect is also exerted on any ordinarydermatomycosis. Therefore, the pharmaceutical medicament preparation,which is directed to the dermatomycosis and which fulfills theconstruction of the present invention, also belongs to the technicalscope of the present invention. The dermatomycosis as described abovecan be exemplified, for example, by the tinea pedis and thetrichophytosis of the propagation in horny substance type appearing, forexample, in the heel and being included in the tinea pedis. As for thedermatomycosis described above, it is preferable to make the applicationto the trichophytosis of the propagation in horny substance type onwhich any ordinary agent or drug hardly exerts the effect, because theeffect of the present invention remarkably arises.

The mode of use can be appropriately selected while considering, forexample, the body weight, the age, the sexuality, and the symptoms orcondition of the patient. However, in the case of an adult, it ispreferable to administer luliconazole in an amount of 0.01 to 1 g perday in ordinary cases. An amount of use of luliconazole ordinarily usedfor a disease caused by any fungus can be used as a reference.

For example, in the case of any preparation for external use, it ispossible to exemplify the application in an appropriate amount to thedisease portion once or several times a day. It is preferable that thetreatment as described above is performed every day. In particular, inthe case of the tinea unguium, luliconazole as the active ingredient,which is in an amount that cannot be brought about by any ordinarypharmaceutical preparation, can be transferred into the nail.Accordingly, the tinea unguium can be cured by means of only theexternal administration without taking any antifungal agent for a longperiod of time. Further, the recurrence and the reinfection cause greatproblems in relation to the tinea unguium. However, it is possible toavoid the recurrence and the reinfection as described above byadministering the pharmaceutical medicament preparation of the presentinvention for 1 week to 2 weeks after the quietness of symptoms. In sucha mode, the pharmaceutical medicament preparation of the presentinvention has the preventive effect.

<3> Index Substance of the Present Invention

The index substance of the present invention is an index substance ofthe stability of a luliconazole pharmaceutical preparation, and includesthe amide form of luliconazole of the above-indicated structure.

The index substance of the stability complements the evaluation of thestability that uses the SE form of luliconazole and the Z form ofluliconazole as index substances.

The wording “complement the evaluation of the stability” means that theindex substance of the present invention can be used as an indexsubstance of the stability of a luliconazole pharmaceutical preparationtogether with the SE form of luliconazole and the Z form ofluliconazole.

EXAMPLES

The present invention will be explained in further detail below asexemplified by Examples.

Example 1

One kilogram (1 kg) of luliconazole was dissolved in a solution ofethanol containing 10% water, and 10 g of silica gel was added thereto,followed by being heated and refluxed for 1 hour. After cooling, silicagel was filtrated off. An obtained filtrate was concentrated, followedby being purified by means of silica gel column chromatography to obtain46.41 g of crude amide form product. This product was recrystallizedthree times from ethanol, and 2.6 g of purified product was obtained.The characteristic values thereof were as follows.

¹H-NMR (CDCl₃, ppm): 3.617 (dd, 1H), 3.639 (dd, 1H), 5.554 (dd, 1H),6.993 (s, 1H), 7.231 to 7.311 (m, 2H), 7.447 to 7.664 (m, 3H); m.p.: 238to 244° C.

Example 2

Luliconazole pharmaceutical preparation 1 was manufactured in accordancewith a formulation shown below. That is, formulation components wereheated, stirred, and solubilized, followed by being stirred and cooledto room temperature to obtain the luliconazole pharmaceuticalpreparation. The luliconazole pharmaceutical preparation was storedunder a temperature condition at 60° C. for 3 weeks, and thepharmaceutical preparation after storage was confirmed by means of theHPLC method. As a result, three peaks were confirmed other than the peakof luliconazole, and compounds corresponding to these peaks werepurified by column chromatography, and the structures thereof weredetermined by NMR and mass analysis. The amide form was produced in thelargest amount. That is, according to this fact, it is confirmed thatthe amide form is the important related substance depending on thesystem.

HPLC condition: column: Inertsil ODS-2 4.6×150 mm, column temperature:40° C., mobile phase: solution of 0.13% sodium undecan-1-sulfonatemixture (water/acetonitrile/acetic acid (100) (54:45:1, v/v/v)), flowrate: 1.0 mL/min., detection: 295 nm.

Further, the contents of the SE form and the Z form were measured bymeans of HPLC with the following HPLC condition. Column: CHIRALCEL OD-RH4.6×150 mm, column temperature: 35° C., mobile phase: mixture ofmethanol/1.80 potassium hexafluorophosphate solution (83:17, v/v)), flowrate: 0.56 mL/min., detection: 295 nm.

TABLE 1 Component % by mass Luliconazole 1 Diisopropyl adipate 5 Benzylalcohol 4 Polyethylene glycol 400 30 Ethanol 60 <Related substance>Result Peak area ratio with respect Peak of identification to peak ofluliconazole (%) Peak 1 SE form 0.4 Peak 2 Z form 0.1 Peak 3 amide form1.2

Example 3

Pharmaceutical preparations 2 and 3 were manufactured in the same manneras in Example 2. The amide form was measured therefor in the same manneras described above after the storage at 60° C. for 3 weeks as well.Results are shown in Table 2. Accordingly, it is confirmed that1,3-butanediol is the factor of the production of the amide form. Inthis way, it is confirmed that the amide form can be also used as theindex to discriminate the factor to suppress the stability.

TABLE 2 Pharmaceutical Pharmaceutical preparation 2 preparation 3Formulation component (% by mass) (% by mass) Luliconazole 1 1Polypropylene glycol* 20 Benzyl alcohol 4 4 Diisopropyl adipate 5 51,3-Butanediol 30 Water 30 30 Ethanol 30 40 Amount of production 0.860.32 of amide form Amount of production 0.38 0.44 of SE form Amount ofproduction 0.12 0.08 of Z form (% by mass) (% by mass) *Average moleculeweight was 2000

Example 4

Pharmaceutical preparation 4 was manufactured in accordance with aformulation shown below. Also in this case, it is confirmed that theproduction of the amide form is suppressed under a storage condition at60° C. for 3 weeks. In relation thereto, it is considered that this iscaused by the addition of polyethylene glycol 400. Accordingly, it isconsidered that polyethylene glycol has the action of suppressing theproduction of the amide form as that of polypropylene glycol.

TABLE 3 Formulation component (% by mass) Luliconazole 5 Propylenecarbonate 5 Benzyl alcohol 2 Lactic acid 4 Polyethylene glycol 400 20Diethyl adipate 24 Polyvinylpyrrolidone 0.25 Ethanol 39.75 Amount ofproduction of 0.02 amide form Amount of production of 0.39 SE formAmount of production of Z 0.05 form (% by mass)

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

INDUSTRIAL APPLICABILITY

The present invention can be applied, for example, to the design of apharmaceutical preparation of luliconazole and the evaluation of thepharmaceutical preparation.

What is claimed is:
 1. A pharmaceutical medicament preparation,comprising: 1) luliconazole; and 2) polyhydric alcohol or ether thereofand dibasic acid ester, wherein upon measurement of an amount ofproduction of an SE form of luliconazole represented by followingformula (2), an amount of production of a Z form of luliconazolerepresented by following formula (3) and an amount of production of anamide form of luliconazole represented by following formula (1) bystorage under a severe condition and an accelerated condition, each ofthe amount of production of the SE form, the amount of production of theZ form and the amount of production of the amide form is not more than5% by mass with respect to a compounded amount of luliconazole.


2. The pharmaceutical medicament preparation according to claim 1,wherein each of the amount of production of the SE form, the amount ofproduction of the Z form and the amount of production of the amide formafter storage under the severe condition and the accelerated conditionis not more than 0.5% by mass with respect to the compounded amount ofluliconazole.
 3. The pharmaceutical medicament preparation according toclaim 1, wherein polyhydric alcohol or ether thereof is selected frompropylene glycol, polyethylene glycol, 1,3-butanediol, diethylene glycolmonoethyl ether, diethylene glycol diethyl ether and polypropyleneglycol; and dibasic acid ester is selected from diethyl adipate,diisopropyl adipate and propylene carbonate.